We wish to determine the in vivo and in vitro interactions with mammalian DNA of (a) the antineoplastic drug cis-DDP and, (b) analagous ruthenium (Ru) ammine and nitrosyl compounds synthesized in this laboratory. Activity of these Ru compounds depends on reduction state. Reduction potential varies according to the ligands attached. Unlike cis-DDP, Ru ions drugs administered clinically would be inactive until reduced in the relatively anoxic milieu of solid tumors. First, using chemical and biophysical techniques, the kinds of reactions of cis-DDP and ruthenium compounds with DNA will be documented. These studies will be performed using exact molar ratios of drugs to DNA. Thus, the stoichiometry, kinetics, and specificity of their reactions with DNA and chromatin will be determined. The biological studies outlined are designed to test our working hypothesis on the increased sensitivity of new DNA and high G-C DNA to platinization. Information obtained from the platinum drug studies will be used in a program for biophysical analysis as well as for screening ruthenium compounds for potential antitumor activity. The ruthenium compounds will be examined for pharmacological activity by testing various doses of the compounds for: (a) toxicity to primary and transformed cell lines in tissue culture, (b) inhibition of DNA, RNA or protein synthesis in such cells, and (c) inhibition of growth of KB (human nasopharangeal carcinoma) cells in suspension culture. We will study the relationship of such activities to chemical properties of the compounds. Special attention will be given to the overall reduction potential and charge, the size, shape and polarity of the complexed ligand base as well as the nature of the "leaving group." The more effective compounds will be further tested to determine the nature of their binding to host macromolecules, especially DNA.